Novel quinuclidine derivatives and their use

ABSTRACT

This invention relates to novel quinuclidine derivatives and their use as pharmaceuticals. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

TECHNICAL FIELD

This invention relates to novel quinuclidine derivatives and their useas pharmaceuticals. Due to their pharmacological profile the compoundsof the invention may be useful for the treatment of diseases ordisorders as diverse as those related to the cholinergic system of thecentral nervous system (CNS), the peripheral nervous system (PNS),diseases or disorders related to smooth muscle contraction, endocrinediseases or disorders, diseases or disorders related toneuro-degeneration, diseases or disorders related to inflammation, pain,and withdrawal symptoms caused by the termination of abuse of chemicalsubstances.

BACKGROUND ART

The endogenous cholinergic neurotransmitter, acetylcholine, exerts itsbiological effect via two types of cholinergic receptors, the muscarinicAcetyl Choline Receptors (mAChR) and the nicotinic Acetyl CholineReceptors (nAChR).

It is well established that muscarinic acetylcholine receptors are ofimportance in relation to memory and cognition, and much research aimedat the development of agents for the treatment of memory relateddisorders have focused on the synthesis of muscarinic acetylcholinereceptor modulators.

Indeed several CNS disorders can be attributed to a cholinergicdeficiency, a dopaminergic deficiency, an adrenergic deficiency or aserotonergic deficiency.

Brown et al. [Brown et al.: Quinuclidine Inhibitors of 2,3-OxidosqualeneCyclase-Lanosterol Synthase: Optimization from Lipid Profiles; J. Med.Chem. 1999 42 1306-1311] describe the synthesis of 3-substitutedquinuclidine derivatives useful as inhibitors of the cholesterolbiosynthesis. An effect on the nicotinic and/or the monoamine receptorsis not reported.

SUMMARY OF THE INVENTION

The present invention is devoted to the provision of new quinuclidinederivatives that are modulators of the nicotinic and/or of the monoaminereceptors, and which modulators are useful for the treatment of diseasesor disorders related to the cholinergic receptors, and in particular thenicotinic acetylcholine receptor, the monoamine receptors, in particularthe serotonin receptor (5-HTR), the dopamine receptor (DAR) and thenorepinephrine receptor (NER), and of the biogenic amine transportersfor serotonin (5-HT), dopamine (DA) and norepinephrine (NE).

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

The compounds of the invention may also be useful as diagnostic tools ormonitoring agents in various diagnostic methods, and in particular forin vivo receptor imaging (neuroimaging), and they may be used inlabelled or unlabelled form.

Accordingly, in its first aspect the invention provides quinuclidinederivatives represented by Formula I

an enantiomer thereof, or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an onium saltthereof, wherein,

represents an optional double bond;

n is 1, 2or 3;

X represents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—,—SO—, —SO₂—, —CH₂—, —S—CH₂—CH₂—, —CH₂—, —C(═CH₂)—,—NH—, —N(alkyl)-,—C(═O)—, —C(═S)—,

A represents a monocyclic or polycyclic, carbocyclic or heterocyclicgroup, optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl;

provided, however,

if X represents O or S;

then A is not phenyl or phenyl substituted with anything other than aphenyl group (i.e. a biphenyl group).

In another aspect the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of the quinuclidinederivative of the invention.

In a third aspect the invention relates to the use of the quinuclidinederivative of the invention, or a pharmaceutically-acceptable additionsalt thereof, for the manufacture of a pharmaceuticalcomposition/medicament for the treatment, prevention or alleviation of adisease or a disorder or a condition of a mammal, including a human,which disease, disorder or condition is responsive to the action of anicotinic acetylcholine receptor modulator.

In a further aspect the invention provides a method of the treatment oralleviation of a disease or disorder of a living animal body, includinga human, which disease or disorder is responsive to the action of anicotinic acetylcholine receptor modulator, which method comprises thestep of administering to such a living animal body, including a human,in need thereof a therapeutically effective amount of the quinuclidinederivative of the invention.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

Quinuclidine Derivatives

In its first aspect, the present invention provides novel quinuclidinederivatives represented by Formula I

an enantiomer thereof, or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an onium saltthereof, wherein,

represents an optional double bond;

n is 1, 2or 3;

X represents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—,—SO—, —SO₂—, —CH₂—, —S—CH₂—CH₂—, —CH₂—, —C(═CH₂)—,—NH—, —N(alkyl)-,—C(═O)—, —C(═S)—,

A represents a monocyclic or polycyclic, carbocyclic or heterocyclicgroup, optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl;

provided, however,

if X represents O or S;

then A is not phenyl or phenyl substituted with anything other than aphenyl group (i.e. if X represents O or S, and A represents a phenylgroup, then this phenyl group must be a biphenyl group only).

In a preferred embodiment the quinuclidine derivative of the inventionis a compound of Formula I, wherein

represents a single (covalent) bond.

In another preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein n is 1, 2 or 3.

In a third preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein X represents a linkerselected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—, and —CH₂—. In a morepreferred embodiment X represents a linker selected from —O—, —O—CH₂—,and —O—CH₂—CH₂—.

In a fourth preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein A represents a monocyclicor polycyclic carbocyclic group selected from phenyl; indanyl, inparticular 4-indanyl and 5-indanyl; indenyl, in particular 1-indenyl,2-indenyl and 3-indenyl; naphthyl, in particular 1-naphthyl and2-naphthyl; 5,6,7,8-tetrahydro-naphthyl, in particular5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl;azulenyl, in particular 1-azulenyl, 2-azulenyl and 3-azulenyl; andfluorenyl, in particular 1-fluorenyl, 2-fluorenyl, 3-fluorenyl and4-fluorenyl; and anthracenyl, in particular 1-anthracenyl and2-anthracenyl; which carbocyclic group is optionally substituted one ortwo times with substituents selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl,alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo,CF₃, CN, NO₂, NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.

In a fifth preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein A represents an aromaticmonocyclic or polycyclic carbocyclic group selected from phenyl;indenyl, in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, inparticular 1-naphthyl and 2-naphthyl; azulenyl, in particular1-azulenyl, 2-azulenyl and 3-azulenyl; and anthracenyl, in particular1-anthracenyl and 2-anthracenyl; which aromatic carbocyclic group isoptionally substituted one or two times with substituents selected fromthe group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy,cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂, NH₂, carboxy,carbamoyl, amido, sulfamoyl, and phenyl.

In a most preferred embodiment the quinuclidine derivative of theinvention of Formula I is

(±)-3-(2-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(3-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(4-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(4-Phenylphenyl-methoxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(Naphthalen-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(5,6,7,8-Tetrahydro-2-naphthyloxy)-1-aza-bicyclo[2.2.2]octane; or

(±)-3-(5-Indanyloxy)-1-aza-bicyclo[2.2.2]octane;

or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.

In a sixth preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein A represents a monocyclicor polycyclic heterocyclic group selected from pyridyl, in particularpyrid-2-yl, pyrid-3-yl and pyrid-4-yl; thienyl, in particular thien-2-yland thien-3-yl; furanyl, in particular furan-2-yl and furan-3-yl;pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl,in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl,in particular 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl,1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl; quinolinyl, inparticular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yland quinolin-6-yl; quinoxalinyl, in particular quinoxalin-2-yl andquinoxalin-3-yl; benzimidazolyl, in particular benzimidazol-2-yl;benzoxazolyl, in particular benzoxazol-2-yl; benzthiazolyl, inparticular benzthiazol-2-yl; which monocyclic or polycyclic heterocyclicgroup is optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.

In a seventh preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein A represents a monocyclicheterocyclic group selected from pyridyl, in particular pyrid-2-yl,pyrid-3-yl and pyrid-4-yl; thienyl, in particular thien-2-yl andthien-3-yl; furanyl, in particular furan-2-yl and furan-3-yl;pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl,in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl,in particular 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl,1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl; which monocyclicheterocyclic group is optionally substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,alkoxy, cycloalkoxy, halo, CF₃, CN, NO₂, NH₂, phenyl, 2-thienyl,3-thienyl, 2-furanyl, 3furanyl, and 3-pyridinyl, which phenyl,2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, and 3-pyridinyl groups mayoptionally be substituted one or two times with substituents selectedfrom the group consisting of alkyl, cycloalkyl, alkoxy, halo, CF₃, CN,NO₂, NH₂, and phenyl.

In a most preferred embodiment the quinuclidine derivative of theinvention of Formula I is

(±)-3-(3,4,5-Trichloro-thien-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(5-Bromo-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(5-Phenyl-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-[5-(2,4-Difluoro-phenyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[5-(3-Thienyl)-thiazol-2-yloxy]-1-aza-bicydo[2.2.2]octane;

(±)-3-[5-(2-Thienyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[5-(3-Furanyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[5-(3-Pyridyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(6-Bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(6-Phenyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-[6-(3-Thienyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[6-(2-Thienyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[6-(2-Furanyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[6-(3-Furanyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-[6-(3-Pyridyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;

(±)-3-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(5-Phenyl-1,2,4-thiadiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane; or

(±)-3-[5-(2-Thienyl)-1,3,4-thiadiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;

or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.

In an eight preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula I, wherein A represents a polycyclicheterocyclic group selected from indolyl, in particular indol-2-yl andindol-3-yl; isoindolyl, in particular isoindol-2-yl; quinolinyl, inparticular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yland quinolin-6-yl; quinoxalinyl, in particular quinoxalin-2-yl andquinoxalin-3-yl; benzimidazolyl, in particular benzimidazol-2-yl;benzoxazolyl, in particular benzoxazol-2-yl; benzthiazolyl, inparticular benzthiazol-2-yl; benzisothiazolyl, in particularbenzisothiazol-3-yl; benztriazolyl, in particular1,2,3-benztriazol-1-yl; imidazo[1,2-b]pyridazinyl, in particularimidazo[1,2-b]pyridazin-6-yl; dibenzofuranyl, in particulardibenzofuran-2-yl; which monocyclic or polycyclic heterocyclic group isoptionally substituted one or more times with substituents selected fromthe group consisting of alkyl, cycloalkyl, alkoxy, cycloalkoxy, halo,CF₃, CN, NO₂, NH₂, and phenyl, which phenyl group may optionally besubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, alkoxy, halo, CF₃, CN, NO₂, NH₂, andphenyl.

In a most preferred embodiment the quinuclidine derivative of theinvention of Formula I is

(±)-3-[(1,3-Dione)-2-isoindolyl-methoxy]-1-azabicyclo[2.2.2]octane;

(±)-3-[(1,3-Dione)-2-isoindolyl-ethoxy]-1-azabicyclo[2.2.2]octane;

(±)-3-(2-Quinolinyloxy)-1-aza-bicyclo[2.2.2)octane;

(±)-3-(2-Quinolinyloxy)-1-aza-bicyclo[2.2.2]octane methylium iodide;

(±)-3-(6-Quinolinyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(2-Quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(2-Quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane methylium iodide;

(±)-3-(3-Chloro-2-quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(3-Methoxy-2-quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(Benzoxazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±) -3-(Benzothiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(6-Chloro-benzothiazol-2-yloxy)-1-aza-bicyclo[2.2.2octane;

(±)-3-(1,2-Benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(1,2-Benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane;

(±)-3-(1-Methyl-benzoimidazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane; or

(±)-3-(Benzotriazol-1-yloxy)-1-azabicyclo[2.2.2]octane;

or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.

In another preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula II

wherein

represents an optional double bond;

n is 1, 2 or 3;

X represents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—,—SO—, —SO₂—, —CH₂—, —S—CH₂—CH₂—, —CH₂—, —C(═CH₂)—,—NH—, —N(alkyl)-,—C(═O)—, —C(═S)—,

Y represents O, S, SO₂, or NR′, wherein R′ represents hydrogen or alkyl.

In a more preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula II, wherein

represents a single (covalent) bond.

In another preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula II, wherein n is 1,2 or 3.

In a third preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula II, wherein Xrepresents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—, and—CH₂—.

In a fourth preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula II, wherein Yrepresents O, S, SO₂, or NR′, wherein R′ represents hydrogen or alkyl.

In a most preferred embodiment the quinuclidine derivative of theinvention of Formula II is

(±)-3-(Dibenzofuran-2-yloxy)-1-azabicyclo[2.2.2]octane;

or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.

In yet another preferred embodiment the quinuclidine derivative of theinvention is a compound of Formula III

wherein

represents an optional double bond;

n is 1, 2or 3;

X represents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—,—SO—, —SO₂—, —CH₂—, —S—CH₂—CH₂—, —CH₂—, —C(═CH₂)—,—NH—, —N(alkyl)-,—C(═O)—, —C(═S)—,

B represents a monocyclic or polycyclic, carbocyclic or heterocyclicgroup, optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.

In a more preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula III, wherein

represents a single (covalent) bond.

In another preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula III, wherein n is1, 2 or 3.

In a third preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula III, wherein Xrepresents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—, and—CH₂—.

In a fourth preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula III, wherein Brepresents a monocyclic or polycyclic, carbocyclic or heterocyclicgroup, optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.

In a fifth preferred embodiment of this aspect the quinuclidinederivative of the invention is a compound of Formula III, wherein Brepresents a phenyl group, which phenyl is optionally substituted one ortwo times with substituents selected from the group consisting of alkyl,cycloalkyl, alkoxy, cycloalkoxy, halo, CF₃, CN, NO₂, NH₂, and phenyl.

In a most preferred embodiment the quinuclidine derivative of theinvention of Formula III is

(±)-3-(2-Phenyl-imidazo[1,2-b]pyridazin-6-yloxy)-1-azabicyclo[2.2.2]octane;

or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.

Any combination of two or more of the embodiments described herein isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromoor iodo. Thus a trihalomethyl group represents e.g. a trifluoromethylgroup, a trichloromethyl group, and similar trihalo-substituted methylgroups.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₄₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In another preferred embodiment of this invention alkyl represents a C₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

In the context of this invention a cycloalkyl-alkyl group designates acycloalkyl group as defined above, which cycloalkyl group is substitutedon an alkyl group as also defined above. Examples of preferredcycloalkyl-alkyl groups of the invention include cyclopropylmethyl andcyclopropylethyl.

In the context of this invention an alkoxy group designates an“alkyl-O—” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy groups of the invention include methoxy and ethoxy.

In the context of this invention a hydroxy-alkoxy group designates analkoxy group as defined above, which alkoxy group is substituted withone or more hydroxy groups. Preferred hydroxy-alkoxy groups of theinvention include 2-hydroxy-ethoxy, 3-hydroxy-propoxy, 4-hydroxy-butoxy,5-hydroxy-pentoxy and 6-hydroxy-hexoxy.

In the context of this invention a cycloalkoxy group designates a“cycloalkyl-O—” group, wherein cycloalkyl is as defined above.

In the context of this invention an alkoxy-alkyl group designates an“alkyl-O-alkyl-” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy-alkyl groups of the invention include methoxy-methyl,methoxy-ethyl, ethoxy-methyl, and ethoxy-ethyl.

In the context of this invention an alkoxy-alkoxy group designates an“alkyl-O-alkyl-O—” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy-alkoxy groups of the invention include methoxy-methoxy,methoxy-ethoxy, ethoxy-methoxy, and ethoxy-ethoxy.

In the context of this invention a cycloalkoxy-alkyl group designates a“cycloalkyl-O-alkyl” group, wherein cycloalkyl and alkyl are as definedabove.

In the context of this invention a cycloalkoxy-alkoxy group designates a“cycloalkyl-O-alkyl-O—” group, wherein cycloalkyl and alkyl are asdefined above.

In the context of this invention a mono- or polycyclic carbocyclic groupis a mono- or polycyclic carbocyclic group holding carbon only as ringatom. The ring structure may in particular be aromatic (i.e. an arylgroup), or saturated or partially saturated.

Preferred mono- or polycyclic carbocyclic groups of the inventioninclude phenyl; indanyl, in particular 4-indanyl and 5-indanyl; indenyl,in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, inparticular 1-naphthyl and 2-naphthyl; 5,6,7,8-tetrahydro-naphthyl, inparticular 5,6,7,8-tetrahydro-1-naphthyl and5,6,7,8-tetrahydro-2-naphthyl; azulenyl, in particular 1-azulenyl,2-azulenyl and 3-azulenyl; fluorenyl, in particular 1-fluorenyl,2-fluorenyl, 3-fluorenyl and 4fluorenyl; and anthracenyl, in particular1-anthracenyl and 2-anthracenyl.

The mono- or polycyclic carbocyclic group may in particular be anaromatic group (aryl). Preferred aryl groups of the invention includephenyl; indenyl, in particular 1-indenyl, 2-indenyl and 3-indenyl;naphthyl, in particular 1-naphthyl and 2-naphthyl; azulenyl, inparticular 1-azulenyl, 2-azulenyl and 3-azulenyl; and anthracenyl, inparticular 1-anthracenyl and 2-anthracenyl.

In the context of this invention a mono- or polycyclic heterocyclicgroup is a mono- or polycyclic compound, which holds one or moreheteroatoms in its ring structure. The term poly-heterocyclic groupsincludes benzo-fused five- and six-membered heterocyclic ringscontaining one or more heteroatoms. Preferred heteroatoms includenitrogen (N), oxygen (O), and sulphur (S). One or more of the ringstructures may in particular be aromatic (i.e. a heteroaryl).

Preferred monocyclic heterocyclic groups of the invention includepyridyl, in particular pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; thienyl,in particular thien-2-yl and thien-3-yl; furanyl, in particularfuran-2-yl and furan-3-yl; pyridazinyl, in particular pyridazin-3-yl andpyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl andthiazol-5-yl; and thiadiazolyl, in particular 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl.

Preferred polycyclic heterocyclic of the invention include indolyl, inparticular indol-2-yl and indol-3-yl; isoindolyl, in particularisoindol-2-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl,quinolin-4-yl, quinolin-5-yl and quinolin-6-yl; quinoxalinyl, inparticular quinoxalin-2-yl and quinoxalin-3-yl; benzimidazolyl, inparticular benzimidazol-2-yl; benzoxazolyl, in particularbenzoxazol-2-yl; benzthiazolyl, in particular benzthiazol-2-yl;benzisothiazolyl, in particular benzisothiazol-3-yl; benztriazolyl, inparticular 1,2,3-benztriazol-1-yl; imidazo[1,2-b]pyridazinyl, inparticular imidazo[1,2-b]pyridazin-6-yl; and dibenzofuranyl, inparticular dibenzofuran-2-yl.

Pharmaceutically Acceptable Salts

The quinuclidine derivative of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the quinuclidine derivative of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulphonate derived from benzensulphonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulphonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a chemicalcompound of the invention include, without limitation, the sodium, thepotassium, the calcium, the magnesium, the zinc, the aluminium, thelithium, the choline, the lysine, and the ammonium salt, and the like,of a chemical compound of the invention containing an anionic group.Such cationic salts may be formed by procedures well known and describedin the art.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts(aza-onium salts). Preferred aza-onium salts include the alkyl-oniumsalts, in particular the methyl- and the ethyl-onium salts; thecycloalkyl-onium salts, in particular the cyclopropyl-onium salts; andthe cycloalkylalkyl-onium salts, in particular thecyclopropyl-methyl-onium salts.

Steric Isomers

The quinuclidine derivatives of the present invention may exist in (+)and (−) forms as well as in racemic forms (±). The racemates of theseisomers and the individual isomers themselves are within the scope ofthe present invention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or l- (tartrates, mandelates,or camphorsulphonate) salts for example.

The quinuclidine derivatives of the present invention may also beresolved by the formation of diastereomeric amides by reaction of thechemical compounds of the present invention with an optically activeactivated carboxylic acid such as that derived from (+) or (−)phenylalanine, (+) or (−) phenylglycine, (+) or (−) camphanic acid or bythe formation of diastereomeric carbamates by reaction of the chemicalcompound of the present invention with an optically active chloroformateor the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Methods of Preparation

The quinuclidine derivatives of the invention may be prepared byconventional methods for chemical synthesis, e.g. those described in theworking examples. The starting materials for the processes described inthe present application are known or may readily be prepared byconventional methods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

The present invention relates to novel quinuclidine derivatives, whichare found to be cholinergic ligands at the nicotinic acetylcholinereceptors (nAChR), and modulators of the monoamine receptors, inparticular the biogenic amine transporters such as the serotoninreceptor (5-HTR), the dopamine receptor (DAR) and the norepinephrinereceptor (NER), and of the biogenic amine transporters for serotonin(5-HT), dopamine (DA) and norepinephrine (NE). Also preferredquinuclidine derivatives of the invention show selective α7 activity, asshown in the working examples. The compounds of the present inventionmay in particular be agonists, partial agonists, antagonists andallosteric modulators of the receptor.

Due to their pharmacological profile the quinuclidine derivatives of theinvention may be useful for the treatment of diseases or conditions asdiverse as CNS related diseases, PNS related diseases, diseases relatedto smooth muscle contraction, endocrine disorders, diseases related toneuro-degeneration, diseases related to inflammation, pain, andwithdrawal symptoms caused by the termination of abuse of chemicalsubstances.

In a preferred embodiment the quinuclidine derivatives of the inventionare used for the treatment of diseases, disorders, or conditionsrelating to the central nervous system. Such diseases or disordersincludes anxiety, cognitive disorders, learning deficit, memory deficitsand dysfunction, Alzheimer's disease, attention deficit, attentiondeficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington'sdisease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette'ssyndrome, psychosis, depression, mania, manic depression, schizophrenia,obsessive compulsive disorders (OCD), panic disorders, eating disorderssuch as anorexia nervosa, bulimia and obesity, narcolepsy, nociception,AIDS-dementia, senile dementia, periferic neuropathy, autism, dyslexia,tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumaticsyndrome, social phobia, sleeping disorders, pseudodementia, Ganser'ssyndrome, pre-menstrual syndrome, late luteal phase syndrome, chronicfatigue syndrome, mutism, trichotillomania, and jet-lag.

In a preferred embodiment diseases, disorders, or conditions relating tothe central nervous system for which the quinuclidine derivatives of theinvention are used are cognitive disorders, psychosis, schizophreniaand/or depression.

In another preferred embodiment the quinuclidine derivatives of theinvention may be useful for the treatment of diseases, disorders, orconditions associated with smooth muscle contractions, includingconvulsive disorders, angina pectoris, premature labour, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, and erectile difficulty.

In yet another preferred embodiment the quinuclidine derivatives of theinvention may be useful for the treatment of endocrine disorders, suchas thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In still another preferred embodiment the quinuclidine derivatives ofthe invention may be useful for the treatment of neurodegenerativedisorders, including transient anoxia and induced neurodegeneration.

In even another preferred embodiment the quinuclidine derivatives of theinvention may be useful for the treatment of inflammatory diseases,disorders, or conditions, including inflammatory skin disorders such asacne and rosacea, Chron's disease, inflammatory bowel disease,ulcerative colitis, and diarrhoea.

In still another preferred embodiment the quinuclidine derivatives ofthe invention may be useful for the treatment of mild, moderate or evensevere pain of acute, chronic or recurrent character, as well as paincaused by migraine, postoperative pain, and phantom limb pain. The painmay in particular be neuropathic pain, chronic headache, central pain,pain related to diabetic neuropathy, to post therapeutic neuralgia, orto peripheral nerve injury.

Finally the quinuclidine derivatives of the invention may be useful forthe treatment of withdrawal symptoms caused by termination of use ofaddictive substances. Such addictive substances include nicotinecontaining products such as tobacco, opioids such as heroin, cocaine andmorphine, benzodiazepines and benzodiazepine-like drugs, and alcohol.Withdrawal from addictive substances is in general a traumaticexperience characterised by anxiety and frustration, anger, anxiety,difficulties in concentrating, restlessness, decreased heart rate andincreased appetite and weight gain.

In this context “treatment” covers treatment, prevention, prophylacticsand alleviation of withdrawal symptoms and abstinence as well astreatment resulting in a voluntary diminished intake of the addictivesubstance.

In another aspect, the quinuclidine derivatives of the invention areused as diagnostic agents, e.g. for the identification and localisationof nicotinic receptors in various tissues.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thequinuclidine derivatives of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the quinuclidine derivative together with one ormore pharmaceutically acceptable carriers therefore, and, optionally,other therapeutic and/or prophylactic ingredients, know and used in theart. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and not harmfulto the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition of the inventioncan be manufactured by a person skilled in the art by use of standardmethods and conventional techniques appropriate to the desiredformulation. When desired, compositions adapted to give sustainedrelease of the active ingredient may be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or conditions as diverse as CNSrelated diseases, PNS related diseases, diseases related to smoothmuscle contraction, endocrine disorders, diseases related toneuro-degeneration, diseases related to inflammation, pain, andwithdrawal symptoms caused by the termination of abuse of chemicalsubstances.

In another aspect the invention provides methods of the treatment,prevention or alleviation of diseases or disorders or conditions of aliving animal body, including a human, which disease or disorder isresponsive to the action of a monoamine receptor modulator, and whichmethod comprises the step of administering to such a living animal body,including a human, in need thereof a therapeutically effective amount ofthe quinuclidine derivative of the invention.

In the context of this invention the term “treating” covers treatment,prevention, prophylaxis or alleviation, and the term “disease” coversillnesses, diseases, disorders and conditions related to the disease inquestion.

It is at present contemplated that a suitable dosage lies within therange of from about 0.1 to about 500 milligram of active substancedaily, more preferred of from about 10 to about 70 milligram of activesubstance daily, administered once or twice a day, dependent as usualupon the exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

General Remarks:

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulfatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

Method A

(±)-3-(Naphthalen-2-yloxy)-1-aza-bicyclo[2.2.2]octane fumaric acid salt(Compound A1)

To a mixture of 2-naphthol (5.0 g, 34.5 mmol), (±)-3-quinuclidinol (2.94g, 23.1 mmol), triphenylphosphine (9.0 g, 34.5 mmol) and tetrahydrofuran(100 ml) was added: diethylazodicarboxylate (5.4 ml, 34.5 mmol) at roomtemperature during 30 minutes. The reaction mixture was allowed to stirfor 20 hours at 50° C. Aqueous sodium hydroxide (100 ml, 1 M) was added.The mixture was extracted with dichloromethane (3×100 ml).Chromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 3.7 g (43%). Mp 140.9-141.60° C.

(±)-3-(4-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane fumaric acid salt(Compound A2)

Was prepared according to method A from 4-phenylphenol. Mp 173.5-185.1°C.

(±)-3-(3-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane free base (CompoundA3)

Was prepared according to method A from 3-phenylphenol. The product wasisolated as an oil.

(±)-3-(2-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane fumaric acid salt(Compound A4)

Was prepared according to method A from 2-phenylphenol. Mp 125.4° C.

(±)-3-(6-Quinolinoxy)-1-aza-bicyclo[2.2.2]octane fumaric acid salt(Compound A5)

Was prepared according to method A from 6-hydroxyquinoline. Mp146.0-147.0° C.

(±)-3-(5-Indanyloxy)-1-aza-bicyclo[2.2.2]octane fumaric acid salt(Compound A6)

Was prepared according to method A from 5-indanol. Mp 149.3-150.5° C.

(±)-3-(5,6,7,8-Tetrahydro-2-naphthyloxy)-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound A7)

Was prepared according to method A from 5,6,7,8-tetrahydro-2-naphthol.Mp 109.7-111.3° C.

Method B

(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-quinoline fumaric acid salt(Compound B1)

A mixture of (±)-3-quinuclidinol (2.0 g, 15.7 mmol), 2-chloroquinoline(2.6 g, 15.7 mmol) and DMF (30 ml) was stirred at room temperature.Sodium hydride (0.94 g, 23.6 mmol, 60% in oil) was added in smallportions. The reaction mixture was stirred for 1.5 hours at 50° C.Aqueous sodium hydroxide (50 ml, 1 M) was added followed by extractionwith diethyl ether (3×50 ml). The combined ethereal phases were washedwith aqueous sodium hydroxide (2×50 ml, 1 M). The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 4.62 g (79%). Mp 160.0-160.5° C.

(±)-3-(6-Chloro-benzothiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound B2)

Was prepared according to procedure B from 2,6-dichlorobenzothiazole. Mp203-205° C.

(±)-3-(Benzothiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane fumaric acidsalt (Compound B3)

Was prepared according to procedure B from 2-chlorobenzothiazole. Mp173.7-174.2° C.

(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-3-chloro-quinoxaline fumaricacid salt (Compound B4)

Was prepared according to procedure B from 2.3-dichloroquinoxaline. Mp120.8-122.1° C.

(±)-3-(1-Methyl-benzoimidazol-2-yloxy)-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound B5)

Was prepared according to procedure B from2-chloro-1-methylbenzoimidazole. Mp 184.9-185.9° C.

(±)-3-(Benzoxazol-2-yloxy)-1-aza-bicyclo]2.2.2]octane fumaric acid salt(Compound B6)

Was prepared according to procedure B from 2-chlorobenzoxazole. Mp187.2-188.8° C.

(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-quinoxaline fumaric acid salt(Compound B7)

Was prepared according to procedure B from 2-chloroquinoxaline. Mp127.7-128.5° C.

(±)-3-(6-Phenylpyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound B8)

Was prepared according to procedure B from 3-chloro-6-phenylpyridazine.Mp 168.5-172.0° C.

(±)3-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound B9)

Was prepared according to procedure B from2-chloro-5-phenyl-1,3,4-thiadiazole. Mp 168.5-172.0° C.

(±)-3-(5-Bromo-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane fumaric acidsalt (Compound B10)

Was prepared according to procedure B from 2,5-dibromothiazole, using 0°C. as reaction temperature. Mp 157.8-162.1° C.

(±)-3-(1,2-Benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound B11)

Was prepared according to procedure B from3-chloro-1,2-benzoisothiazole. Mp 172.3-173.6° C.

(±)-3-(5-Phenyl-1,2,4-thiadiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound B12)

Was prepared according to procedure B3-chloro-5-phenyl-1,2,4,-thiadiazole. Mp 155.0-159.3° C.

(±)-3-(6-Bromo-Pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound B13)

Was prepared according to procedure B from 3,6-dibromopyridazine. Mp152.8° C.

(±)-3-(6-Chloro-Pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound B14)

Was prepared according to procedure B from 3,6-dichloropyridazine. Mp164-164.5° C.

(±)-3-(3,4,5-Trichloro-2-yloxy)-1-aza-bicyclo[2.2.2]octane fumaric acidsalt (Compound B15)

Was prepared according to procedure B, using the conditions: potassiumtert-butoxide, crown ether (18:6), from tetrachlorothiophene. Mp188-189.4° C.

(±)-3-(3-Methoxy-2-quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound B16)

A mixture of(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-3-chloro-quinoxaline (CompoundB4; 1.38 g, 4.76 mmol), cecium carbonate (1.55 g, 4.76 mmol) andmethanol (15 ml) was stirred for 3 hours at 45° C. Aqueous sodiumhydroxide (50 ml, 1 M) was added followed by extraction with diethylether (3×50 ml). The corresponding salt was obtained by addition of adiethyl ether and methanol mixture (9:1) saturated with fumaric acid.Yield 0.51 g, 27%. Mp 168.5-170.0° C.

(±)-3-[5-(3-Thienyl)-1,3,4-thiadiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound B17)

Was prepared according to procedure B from2-chloro-5-(3-thienyl)-1,3,4-thiadiazole. Mp 186-188° C.

(±)-3-[(1,3-Dione)-2-isoindolyl-methoxy]-1-azabicyclo[2.2.2]octanefumaric acid salt (Compound B18)

Was prepared according to procedure B from N-(2-bromomethyl)-phtalimid.Mp 212-213° C.

(±)-3-[(1,3-Dione)-2-isoindolyl-ethoxy]-1-azabicyclo[2.2.2]octane freebase (Compound B19)

Was prepared according to procedure B from N-(2-bromoethyl)-phtalimid.Isolated as free base, oil.

(±)-3-(Benzotriazol-1-yloxy)-1-azabicyclo[2.2.2]octane fumaric acid salt(Compound B20)

Was prepared according to procedure B from1-(chloromethyl)-1H-benzotriazole Mp 163.3-164.5° C.

Method C

(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-quinoxaline methylium iodidesalt (Compound C1)

A mixture of (±)-3-(quinoxalin-2-yloxy)-1-aza-bicyclo[2.2.2]octane (1.27g, 5.0 mmol) dichloromethane (10 ml) was added at −70° C.: methyliodide(0.31 g, 5.0 mmol) solved in dichloromethane (1.5 ml) was added over 10minutes. The reaction was stirred at −70° C. for 40 minutes. Thereaction mixture was allowed to stir at room temperature for 3 hours.The precipitate was isolated by filtration. Mp 229-230° C.

(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-quinoline methylium iodide(Compound C2)

Was prepared according to method C from(±)-2-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-quinoline. Mp 156.6-175.2° C.

(±)-3-(1,2-Benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane methyliumiodide (Compound C3)

Was prepared according to method C from(±)-3-(1,2-benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane. Mp180.1-186.4° C.

Method D

(±)-3-(5-Phenyl-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane fumaric acidsalt (Compound D1)

A mixture of (±)-3-(5-bromo-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane(1.25 g, 4.32 mmol), phenylboronic acid (0.791 g, 6.48 mmol), Pd(PPh₃)₄(0.150 g, 0.13 mmol), aqueous potassium carbonate (6.5 ml, 2 M),1,3-propanediol (0.97 ml, 13.0 mmol) and 1,2-dimethoxyethane (30 ml) wasstirred at reflux for 15 hours. Aqueous sodium hydroxide (50 ml, 1 M)was added, the mixture was extracted with ethyl acetate (3×50 ml).Chromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound. Yield 3.7 g (43%). Thecorresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 170.9-172.2° C.

(±)-3-[5-(2,4-Difluoro-phenyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound D2)

Was prepared according to method D. Mp 84.3-86.3° C.

(±)-3-[5-(3-Thienyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound D3)

Was prepared according to method D. Mp 68.5-74.3° C.

(±)-3-[5-(2-Thienyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound D4)

Was prepared according to method D. Mp 152.6-154.9° C.

(±)-3-[5-(3-Furanyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound D5)

Was prepared according to method D. Mp 127.6-136.2° C.

(±)-3-[5-(3-Pyridyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane fumaricacid salt (Compound D6)

Was prepared according to method D. Mp 82.7-86.0° C.

(±)-3-[6-(3-Thienyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound D7)

Was prepared according to method D from(±)-3-(6-bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. Mp 197.9°C.

(±)-3-[6-(2-Thienyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound D8)

Was prepared according to method D from(±)-3-(6-bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. Mp180.3-191.1 ° C.

(±)-3-[6-(2-Furanyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound D9)

Was prepared according to method D from(±)-3-(6-bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. Mp175.8-178.2° C.

(±)-3-[6-(3-Furanyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound D10)

Was prepared according to method D from(±)-3-(6-bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. Mp224.8-225.4° C.

(±)-3-[6-(3-Pyridyl)-Pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound D11)

Was prepared according to method D from(±)-3-(6-bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane. Mp137.2-143.2° C.

Method E

(±)-3-(4-Phenylphenyl-methoxy)-1-aza-bicyclo[2.2.2]octane fumaric acidsalt (Compound E1)

A mixture of (±)-3-quinuclidinol (2.0 g, 15.7 mmol),4-phenylbenzylchloride (3.2 g, 15.7 mmol), sodium hydride, 60% with oil(1.26 g, 31.4 mmol) and DMF (30 ml) was at 50° C. for 4.5 hours. Aqueoussodium hydroxide (100 ml, 1 M) was added. The mixture was extracted withdiethyl ether (3×50 ml). Chromatography on silica gel withdichloromethane, methanol and conc. ammonia (89:10:1) gave the titlecompound. Yield 2.0 g (29%).

The corresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 159.8-160.4° C.

The compound may also be named(±)-3-(biphenyl-4-yl-methoxy)-quinuclidine.

Method F

(±)-3-(2-Phenyl-imidazo[1,2-b]pyridazin-6-yloxy)-1-aza-bicyclo[2.2.2]octanefumaric acid salt (Compound F1)

To a mixture of 6-chloro-2-phenyl-imidazo[1,2-b]pyridazin (preparedaccording to J. Heterocycl. Chem. 39, 737, 2002) (3.6 g, 15.7 mmol),(±)-3-quinuclidinol 2.0 g, 15.7 mmol) in DMF (30 ml): sodium hydride(1.26 g, 31.4 mmol) was added over 20 min, at room temperature, followedby stirring at 50° C. for 4 hours. Aqueous sodium hydroxide (100 ml, 1M) was added. The mixture was extracted with diethyl ether (3×100 ml).Chromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound. Yield 2.9 g (57%).

The corresponding salt was obtained by addition of a diethyl ether andmethanol mixture (9:1) saturated with fumaric acid. Mp 211-216° C.

Method G

(±)-3-(Dibenzofuran-2-yloxy)-1-azabicyclo[2.2.2]octane fumaric acid salt(Compound G1)

To a mixture of (±)-3-quinuclidinol (3.0 g, 23.6 mmol),2-hydroxydibenzofuran (4.3 g, 23.6 mmol), triphenylphosphine (9.29 g,35.4 mmol) and THF, was added: diethylazodicarboxylate (6.3 ml, 35.4mmol) over a time period of 40 min at room temperature. The mixture wasstirred at 50° C. for 7 days. Aqueous sodium hydroxide (100 ml, 1 M) wasadded. The mixture was extracted with dichloromethane (3×100 ml).Chromatography on silica gel with dichloromethane, methanol and conc.ammonia (89:10:1) gave the title compound. Yield 2.0 g (29%).

The corresponding fumaric acid salt was obtained by addition of adiethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp131.3-133.8° C.

The compound also may be named(±)-3-(Dibenzofuran-2-yloxy)-quinuclidine.

Biological Activity

In Vitro Inhibition of ³H-α-Bungarotoxine Binding in Rat Brain

In this example the affinity of the compounds of the invention forbinding to α₇-subtype of nicotinic receptors is determined.

α-Bungarotoxine is a peptide isolated from the venom of the Elapidaesnake Bungarus multicinctus. It has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.

³H-α-Bungarotoxine labels nicotinic acetylcholine receptors formed bythe α₇ subunit isoform found in brain and the α₁ isoform in theneuromuscular junction.

Tissue Preparation

Preparations are performed at 0-4° C. Cerebral cortices from male Wistarrats (150-250 g) are homogenised for 10 seconds in 15 ml of 20 mM Hepesbuffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO₄ and 2.5 mM CaCl₂(pH 7.5) using an Ultra-Turrax homogeniser. The tissue suspension issubjected to centrifugation at 27,000×g for 10 minutes. The supernatantis discarded and the pellet is washed twice by centrifugation at27,000×g for 10 minutes in 20 ml of fresh buffer, and the final pelletis then re-suspended in fresh buffer containing 0.01% BSA (35 ml per gof original tissue) and used for binding assays.

Assay

Aliquots of 500 μl of homogenate are added to 25 μl of test solution and25 μl of ³H-α-bungarotoxine (2 nM, final concentration) and mixed andincubated for 2 hours at 37° C. Non-specific binding is determined using(−)-nicotine (1 mM, final concentration). After incubation, the samplesare added 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poureddirectly onto Whatman GF/C glass fibre filters (pre-soaked in 0.1% PEIfor at least 6 hours) under suction, and immediately washed with 2×5 mlice-cold buffer.

The amount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

The test value is given as an IC₅₀ (the concentration of the testsubstance which inhibits the specific binding of ³H-α-bungarotoxin by50%).

The results of these experiments are presented in Table 1 below. TABLE 1Inhibition of ³H-α-Bungarotoxine Binding Compound IC₅₀ No. (μM) A2 0.16B2 0.18 B3 0.17  B17 0.15 D1 0.052 D3 0.11 D4 0.020 D5 0.048 D6 0.18 D70.13 D8 0.053

1-36. (canceled)
 37. A quinuclidine derivative represented by Formula I

an enantiomer thereof, or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an onium saltthereof, wherein,

represents an optional double bond; n is 1, 2 or 3; X represents alinker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—, —SO—, —SO₂—, —CH₂—,—S—CH₂—CH₂—, —CH₂—, —C(═CH₂)—,—NH—, —N(alkyl)-, —C(═O)—, —C(═S)—,

A represents a monocyclic or polycyclic, carbocyclic or heterocyclicgroup, optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl; provided,however, if X represents O or S; then A is not phenyl or phenylsubstituted with anything other than a phenyl group.
 38. Thequinuclidine derivative of claim 37, wherein

represents a single (covalent) bond.
 39. The quinuclidine derivative ofclaim 37, wherein n is 1, 2 or
 3. 40. The quinuclidine derivative ofclaim 37, wherein X represents a linker selected from —O—, —O—CH₂—,—O—CH₂—CH₂—, —S—, and —CH₂—.
 41. The quinuclidine derivative of claim37, wherein A represents a monocyclic or polycyclic carbocyclic groupselected from indanyl, in particular 4-indanyl and 5-indanyl; indenyl,in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, inparticular 1-naphthyl and 2-naphthyl; 5,6,7,8-tetrahydro-naphthyl, inparticular 5,6,7,8-tetrahydro-1-naphthyl and5,6,7,8-tetrahydro-2-naphthyl; azulenyl, in particular 1-azulenyl,2-azulenyl and 3-azulenyl; and fluorenyl, in particular 1-fluorenyl,2-fluorenyl, 3-fluorenyl and 4-fluorenyl; and anthracenyl, in particular1-anthracenyl and 2-anthracenyl; which carbocyclic group is optionallysubstituted one or two times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy,cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂, NH₂, carboxy,carbamoyl, amido, sulfamoyl, and phenyl.
 42. The quinuclidine derivativeof claim 37, wherein A represents an aromatic monocyclic or polycycliccarbocyclic group selected from phenyl; indenyl, in particular1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular 1-naphthyland 2-naphthyl; azulenyl, in particular 1-azulenyl, 2-azulenyl and3-azulenyl; and anthracenyl, in particular 1-anthracenyl and2-anthracenyl; which aromatic carbocyclic group is optionallysubstituted one or two times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy,cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂, NH₂, carboxy,carbamoyl, amido, sulfamoyl, and phenyl.
 43. The quinuclidine derivativeof claim 41, which is(±)-3-(2-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(3-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(4-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(4-Phenylphenyl-methoxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(Naphthalen-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(5,6,7,8-Tetrahydro-2-naphthyloxy)-1-aza-bicyclo[2.2.2]octane; or(±)-3-(5-Indanyloxy)-1-aza-bicyclo[2.2.2]octane; or an enantiomerthereof, or a pharmaceutically-acceptable addition salt thereof, or anonium salt thereof.
 44. The quinuclidine derivative of claim 37, whereinA represents a monocyclic or polycyclic heterocyclic group selected frompyridyl, in particular pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; thienyl,in particular thien-2-yl and thien-3-yl; furanyl, in particularfuran-2-yl and furan-3-yl; pyridazinyl, in particular pyridazin-3-yl andpyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl andthiazol-5-yl; thiadiazolyl, in particular 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl;quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-5-yl and quinolin-6-yl; quinoxalinyl, in particularquinoxalin-2-yl and quinoxalin-3-yl; benzimidazolyl, in particularbenzimidazol-2-yl; benzoxazolyl, in particular benzoxazol-2-yl;benzthiazolyl, in particular benzthiazol-2-yl; which monocyclic orpolycyclic heterocyclic group is optionally substituted one or moretimes with substituents selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl,alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo,CF₃, CN, NO₂, NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, orwith another monocyclic or polycyclic, carbocyclic or heterocyclicgroup, which additional monocyclic or polycyclic, carbocyclic orheterocyclic group may optionally be substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.
 45. Thequinuclidine derivative of claim 37, wherein A represents a monocyclicheterocyclic group selected from pyridyl, in particular pyrid-2-yl,pyrid-3-yl and pyrid-4-yl; thienyl, in particular thien-2-yl andthien-3-yl; furanyl, in particular furan-2-yl and furan-3-yl;pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl,in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl,in particular 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl,1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl; which monocyclicheterocyclic group is optionally substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,alkoxy, cycloalkoxy, halo, CF₃, CN, NO₂, NH₂, phenyl, 2-thienyl,3-thienyl, 2-furanyl, 3-furanyl, and 3-pyridinyl, which phenyl,2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, and 3-pyridinyl groups mayoptionally be substituted one or two times with substituents selectedfrom the group consisting of alkyl, cycloalkyl, alkoxy, halo, CF₃, CN,NO₂, NH₂, and phenyl.
 46. The quinuclidine derivative of claim 45, whichis (±)-3-(3,4,5-Trichloro-thien-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(5-Bromo-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(5-Phenyl-thiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-[5-(2,4-Difluoro-phenyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[5-(3-Thienyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[5-(2-Thienyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[5-(3-Furanyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[5-(3-Pyridyl)-thiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(6-Bromo-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(6-Phenyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-[6-(3-Thienyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[6-(2-Thienyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[6-(2-Furanyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[6-(3-Furanyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-[6-(3-Pyridyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;(±)-3-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(5-Phenyl-1,2,4-thiadiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane; or(±)-3-[5-(2-Thienyl)-1,3,4-thiadiazol-2-yloxy]-1-aza-bicyclo[2.2.2]octane;or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.
 47. The quinuclidine derivative ofclaim 37, wherein A represents a polycyclic heterocyclic group selectedfrom indolyl, in particular indol-2-yl and indol-3-yl; isoindolyl, inparticular isoindol-2-yl; quinolinyl, in particular quinolin-2-yl,quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and quinolin-6-yl;quinoxalinyl, in particular quinoxalin-2-yl and quinoxalin-3-yl;benzimidazolyl, in particular benzimidazol-2-yl; benzoxazolyl, inparticular benzoxazol-2-yl; benzthiazolyl, in particularbenzthiazol-2-yl; benzisothiazolyl, in particular benzisothiazol-3-yl;benztriazolyl, in particular 1,2,3-benztriazol-1-yl;imidazo[1,2-b]pyridazinyl, in particular imidazo[1,2-b]pyridazin-6-yl;dibenzofuranyl, in particular dibenzofuran-2-yl; which monocyclic orpolycyclic heterocyclic group is optionally substituted one or moretimes with substituents selected from the group consisting of alkyl,cycloalkyl, alkoxy, cycloalkoxy, halo, CF₃, CN, NO₂, NH₂, and phenyl,which phenyl group may optionally be substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,alkoxy, halo, CF₃, CN, NO₂, NH₂, and phenyl.
 48. The quinuclidinederivative of claim 47, which is(±)-3-[(1,3-Dione)-2-isoindolyl-methoxy]-1-azabicyclo[2.2 .2]octane;(±)-3-[(1,3-Dione)-2-isoindolyl-ethoxy]- 1-azabicyclo[2.2.2]octane;(±)-3-(2-Quinolinyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(2-Quinolinyloxy)-1-aza-bicyclo[2.2.2]octane methylium iodide;(±)-3-(6-Quinolinyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(2-Quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(2-Quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane methylium iodide;(±)-3-(3-Chloro-2-quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(3-Methoxy-2-quinoxalinyloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(Benzoxazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(Benzothiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(6-Chloro-benzothiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(1,2-Benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(1,2-Benzoisothiazol-3-yloxy)-1-aza-bicyclo[2.2.2]octane;(±)-3-(1-Methyl-benzoimidazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane; or(±)-3-(Benzotriazol-1-yloxy)-1-azabicyclo[2.2.2]octane; or an enantiomerthereof, or a pharmaceutically-acceptable addition salt thereof, or anonium salt thereof.
 49. The quinuclidine derivative of claim 37,represented by Formula III

wherein z,900 represents an optional double bond; n is 1,2 or 3; Xrepresents a linker selected from —O—, —O—CH₂—, —O—CH₂—CH₂—, —S—, —SO—,—SO₂—, —CH₂—, —S—CH₂—CH₂—, —CH₂—, —C(═CH₂)—,—NH—, —N(alkyl)-, —C(═O)—,—C(═S)—,

B represents a monocyclic or polycyclic, carbocyclic or heterocyclicgroup, optionally substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.
 50. Thequinuclidine derivative of claim 49, wherein

represents a single (covalent) bond.
 51. The quinuclidine derivative ofclaim 49, wherein n is 1, 2 or
 3. 52. The quinuclidine derivative ofclaim 49, wherein X represents a linker selected from —O—, —O—CH₂—,—O—CH₂—CH₂—, —S—, and —CH₂—.
 53. The quinuclidine derivative of claim49, wherein B represents a monocyclic or polycyclic, carbocyclic orheterocyclic group, optionally substituted one or more times withsubstituents selected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with anothermonocyclic or polycyclic, carbocyclic or heterocyclic group, whichadditional monocyclic or polycyclic, carbocyclic or heterocyclic groupmay optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy,cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF₃, CN, NO₂,NH₂, carboxy, carbamoyl, amido, sulfamoyl, and phenyl.
 54. Thequinuclidine derivative of claim 53, wherein B represents a phenylgroup, which phenyl is optionally substituted one or two times withsubstituents selected from the group consisting of alkyl, cycloalkyl,alkoxy, cycloalkoxy, halo, CF₃, CN, NO₂, NH₂, and phenyl.
 55. Thequinuclidine derivative of claim 54, which is(±)-3-(2-Phenyl-imidazo[1,2-b]pyridazin-6-yloxy)-1-azabicyclo[2.2.2]octane;or an enantiomer thereof, or a pharmaceutically-acceptable addition saltthereof, or an onium salt thereof.
 56. A pharmaceutical compositioncomprising a therapeutically effective amount of a quinuclidinederivative of claim 37, or a pharmaceutically-acceptable addition saltthereof.
 57. A method of treatment, prevention or alleviation of adisease or a disorder or a condition of a living animal body, includinga human, which disorder, disease or condition is responsive tomodulation of cholinergic receptors and/or monoamine receptors, whichmethod comprises the step of administering to such a living animal bodyin need thereof a therapeutically effective amount of a quinuclidinederivative of claim
 37. 58. The method according to claim 57, whereinthe disease, disorder or condition relates to the central nervoussystem.
 59. The method according to claim 58, wherein the disease,disorder or condition is anxiety, cognitive disorders, learning deficit,memory deficits and dysfunction, Alzheimer's disease, attention deficit,attention deficit hyperactivity disorder (ADHD), Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles de laTourette's syndrome, psychosis, depression, mania, manic depression,schizophrenia, obsessive compulsive disorders (OCD), panic disorders,eating disorders such as anorexia nervosa, bulimia and obesity,narcolepsy, nociception, AIDS-dementia, senile dementia, perifericneuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia,epilepsy, bulimia, post-traumatic syndrome, social phobia, sleepingdisorders, pseudodementia, Ganser's syndrome, pre-menstrual syndrome,late luteal phase syndrome, chronic fatigue syndrome, mutism,trichotillomania, and jet-lag.
 60. The method according to claim 57,wherein the disease, disorder or condition are associated with smoothmuscle contractions, including convulsive disorders, angina pectoris,premature labour, convulsions, diarrhoea, asthma, epilepsy, tardivedyskinesia, hyperkinesia, premature ejaculation, and erectiledifficulty.
 61. The method according to claim 57, wherein the disease,disorder or condition is related to the endocrine system, such asthyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
 62. Themethod according to claim 57, wherein the disease, disorder or conditionis a neurodegenerative disorders, including transient anoxia and inducedneuro-degeneration.
 63. The method according to claim 57, wherein thedisease, disorder or condition is an inflammatory disorder, includinginflammatory skin disorders such as acne and rosacea, Chron's disease,inflammatory bowel disease, ulcerative colitis, and diarrhoea.
 64. Themethod according to claim 57, wherein the disease, disorder or conditionis mild, moderate or even severe pain of acute, chronic or recurrentcharacter, pain caused by migraine, postoperative pain, phantom limbpain, neuropathic pain, chronic headache, central pain, pain related todiabetic neuropathy, to post therapeutic neuralgia, or to peripheralnerve injury.
 65. The method according to claim 57, wherein the disease,disorder or condition is associated with withdrawal symptoms caused bytermination of use of addictive substances, including nicotinecontaining products such as tobacco, opioids such as heroin, cocaine andmorphine, benzodiazepines and benzodiazepine-like drugs, and alcohol.